S-(3-oxopropyl)glutathione | 124521-13-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: S-(3-oxopropyl)glutathione
• 英文别名: acrolein-GSH；S-3-oxopropylglutathione；(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-(3-oxopropylsulfanyl)propan-2-yl]amino]-5-oxopentanoic acid
• CAS: 124521-13-7
• 化学式: C₁₃H₂₁N₃O₇S
• 分子量: 363.392
• InChiKey: RDNSBKKJIQKSJT-IUCAKERBSA-N

物化性质

• 沸点：
  809.4±65.0 °C(Predicted)
• 密度：
  1.397±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  24
• 可旋转键数：
  13
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  201
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  S-(3-oxopropyl)glutathione 在 水 作用下， 生成
  参考文献：
  名称：

  Acrolein Mercapturates: Synthesis, Characterization, and Assessment of Their Role in the Bladder Toxicity of Cyclophosphamide

  摘要：

  Acrolein is the metabolite of cyclophosphamide (CP) believed to be involved in the bladder toxicity associated with this anticancer drug. The mechanism by which this extremely reactive intermediate is delivered to the bladder is not known. Glutathione (GSH) readily conjugates with acrolein, and the acrolein mercapturate S-(3-hydroxypropyl)-N-acetylcysteine (3-hydroxy-PrMCA) has been found in the urine of animals and man given CP. The objectives of this study were to prepare and characterize synthetic standards of the GSH acrolein adduct (3-oxopropyl)glutathione (3-oxoPrGSH), the acrolein mercapturates S-(3-oxopropyl)-N-acetylcysteine (S-oxoPrMCA) and 3-hydroxyPrMCA, and the S-oxidation product of 3-oxoPrMCA (3-oxoPrMCA S-oxide). In addition, the release of acrolein from, and the bladder toxicity of, these conjugates was determined. 3-OxoPrGSH and 3-oxoPrMCA were prepared with a 99% yield by condensing acrolein with GSH and N-acetylcysteine, respectively. 3-HydroxyPrMCA was prepared with a 63% yield by refluxing 3-chloropropanol and N-acetylcysteine in a basic medium. Oxidation of 3-oxoPrMCA with H2O2 was used to prepare 3-oxoPrMCA S-oxide. By decreasing the reaction time to 1 h, and adjusting the ratio of S-oxoPrMCA to H2O2, the yield of 3-oxoPrMCA S-oxide was increased to 96%. The anhydrous aldehyde, 3-oxoPrMCA, afforded characteristic aldehydic proton resonances (H-1 NMR) in deuterated dimethyl sulfoxide. New resonances were observed in deuterated water, indicating a 75% hydration of the aldehyde to the corresponding geminal diol. This phenomenon was enhanced with 3-oxoPrMCA S-oxide where similar to 100% hydration of the aldehyde to the corresponding geminal diol was observed. When incubated at 25 degrees C in 100 mM potassium phosphate buffer containing 1 M KCl, pH 8.0, 3-oxoPrMCA released similar to 6% and 3-oxoPrMCA S-oxide released similar to 16-18% of the theoretical maximum yield of acrolein after 30 min, as indicated by an increase in absorbance at 210 nm and confirmed by trapping this aldehyde as a semicarbazone. There was less than a 2% yield of acrolein from 3-hydroxyPrMCA or 3-oxoPrGSH under similar conditions. At pH 7.4 the release of acrolein from 3-oxoPrMCA and S-oxoPrMCA S-oxide was decreased by 50%. An assay where aldehydes are reacted with m-aminophenol in acid media produced fluorescence consistent with 72%, 46%, 23%, and 1% yields of acrolein from 3-oxoPrMCA S-oxide, 3-oxoPrMCA, 3-oxoPrGSH, and 3-hydroxyPrMCA, respectively. These yields were unaffected by incubation in buffer for up to 2 h. Acrolein, 3-oxoPrMCA S-oxide, S-oxoPrMCA and 3-oxoPrGSH, but not 3-hydroxyPrMCA, damaged the bladder dose-dependently when instilled intravesically in mice at concentrations of 10-20 mM. Potency was acrolein > 3-oxoPrMCA S-oxide > 3-oxoPrMCA > 3-oxoPrGSH. These data support the possibility that a mercapturic acid may be involved in the bladder toxicity of CP.

  DOI：

  10.1021/tx00046a005
• 作为产物：
  描述：

  谷胱甘肽 、 丙烯醛 以 乙醇 、 水 为溶剂， 反应 2.0h， 生成 S-(3-oxopropyl)glutathione
  参考文献：
  名称：

  丙烯醛的维生素 C 缀合物的形成及其对氧磷酶介导的转化为 5,6,7,8-四羟基-4-氧代辛醛

  摘要：

  据报道，维生素 C（抗坏血酸）参与体外迈克尔加成反应，与 α,β-不饱和醛（如丙烯醛）形成维生素 C 缀合物。该研究显示了丙烯醛维生素 C 结合物 (AscACR) 在暴露于丙烯醛二乙酸酯的培养的人类单核细胞 THP-1 细胞中形成和代谢的证据。通过使用18 O 和13C 标记与液相色谱-串联质谱法相结合，显示 AscACR 将抗坏血酸内酯水解转化为中间体羧酸。随后羧酸的脱羧产生 5,6,7,8-四羟基-4-氧代辛醛 (THO)。当 THP-1 细胞用抗坏血酸 (1 mM, 18 h) 预处理，然后暴露于二乙酸丙烯醛时，在细胞裂解物和培养基中检测到 THO 作为其五氟苄基肟衍生物。THO形成需要用抗坏血酸和丙烯醛二乙酸酯处理THP-1细胞。内酯酶、人重组对氧磷酶 1 和 2 促进了 AscACR 形成 THO。THP-1 细胞表现出 PON 活性，这解释了 AscACR 在这些细胞中催化转化为

  DOI：

  10.1021/tx900452j

文献信息

• The Influence of Glutathione and Detoxifying Enzymes on DNA Damage Induced by 2-Alkenals in Primary Rat Hepatocytes and Human Lymphoblastoid Cells
  作者：Gerhard Eisenbrand、Joachim Schuhmacher、Petra Goelzer

  DOI：10.1021/tx00043a005

  日期：1995.1

  The reaction of 2-alkenals with GSH to form GSH conjugates by Michael addition is a major detoxification pathway. The reaction proceeds at a much higher rate under catalysis by glutathione S-transferase (GST) than the non-enzymatic reaction. Oxidation of 2-alkenals to the corresponding acids by cytosolic and microsomal fraction of rat liver also contributes to detoxification. Primary rat hepatocytes rich in GSH and proficient for GST and other metabolizing enzymes consume much more alkenal than human lymphoblastoid cells (Namalva cells), that are poor in GSH and in metabolic activities. In Namalva cells DNA single strand breaks were induced by much lower concentrations of acrolein, crotonaldehyde and (E)-2-hexenal than in primary rat hepatocytes. In both cell systems intracellular GSH depletion by 2-alkenals proceeds in a dose dependent manner, approaching about 20% of pretreatment level before DNA damage becomes detectable. GSH conjugates of(E)-2-hexenal and (2E,6Z)-2,6-nonadienal induce DNA damage in Namalva cells at high concentrations (1.5 mM). In the absence of GSH these conjugates decompose slowly into aldehyde and GSH. Although the rate of decomposition is only about 10(-4) times that of Michael adduct formation, such GSH conjugates could potentially function as transport molecules for 2-alkenals, if they reach tissues low in GSH and GST.
• Acrolein Mercapturates: Synthesis, Characterization, and Assessment of Their Role in the Bladder Toxicity of Cyclophosphamide
  作者：Kumar Ramu、Lucy H. Fraiser、Blain Mamiya、Tamer Ahmed、James P. Kehrer

  DOI：10.1021/tx00046a005

  日期：1995.6

  Acrolein is the metabolite of cyclophosphamide (CP) believed to be involved in the bladder toxicity associated with this anticancer drug. The mechanism by which this extremely reactive intermediate is delivered to the bladder is not known. Glutathione (GSH) readily conjugates with acrolein, and the acrolein mercapturate S-(3-hydroxypropyl)-N-acetylcysteine (3-hydroxy-PrMCA) has been found in the urine of animals and man given CP. The objectives of this study were to prepare and characterize synthetic standards of the GSH acrolein adduct (3-oxopropyl)glutathione (3-oxoPrGSH), the acrolein mercapturates S-(3-oxopropyl)-N-acetylcysteine (S-oxoPrMCA) and 3-hydroxyPrMCA, and the S-oxidation product of 3-oxoPrMCA (3-oxoPrMCA S-oxide). In addition, the release of acrolein from, and the bladder toxicity of, these conjugates was determined. 3-OxoPrGSH and 3-oxoPrMCA were prepared with a 99% yield by condensing acrolein with GSH and N-acetylcysteine, respectively. 3-HydroxyPrMCA was prepared with a 63% yield by refluxing 3-chloropropanol and N-acetylcysteine in a basic medium. Oxidation of 3-oxoPrMCA with H2O2 was used to prepare 3-oxoPrMCA S-oxide. By decreasing the reaction time to 1 h, and adjusting the ratio of S-oxoPrMCA to H2O2, the yield of 3-oxoPrMCA S-oxide was increased to 96%. The anhydrous aldehyde, 3-oxoPrMCA, afforded characteristic aldehydic proton resonances (H-1 NMR) in deuterated dimethyl sulfoxide. New resonances were observed in deuterated water, indicating a 75% hydration of the aldehyde to the corresponding geminal diol. This phenomenon was enhanced with 3-oxoPrMCA S-oxide where similar to 100% hydration of the aldehyde to the corresponding geminal diol was observed. When incubated at 25 degrees C in 100 mM potassium phosphate buffer containing 1 M KCl, pH 8.0, 3-oxoPrMCA released similar to 6% and 3-oxoPrMCA S-oxide released similar to 16-18% of the theoretical maximum yield of acrolein after 30 min, as indicated by an increase in absorbance at 210 nm and confirmed by trapping this aldehyde as a semicarbazone. There was less than a 2% yield of acrolein from 3-hydroxyPrMCA or 3-oxoPrGSH under similar conditions. At pH 7.4 the release of acrolein from 3-oxoPrMCA and S-oxoPrMCA S-oxide was decreased by 50%. An assay where aldehydes are reacted with m-aminophenol in acid media produced fluorescence consistent with 72%, 46%, 23%, and 1% yields of acrolein from 3-oxoPrMCA S-oxide, 3-oxoPrMCA, 3-oxoPrGSH, and 3-hydroxyPrMCA, respectively. These yields were unaffected by incubation in buffer for up to 2 h. Acrolein, 3-oxoPrMCA S-oxide, S-oxoPrMCA and 3-oxoPrGSH, but not 3-hydroxyPrMCA, damaged the bladder dose-dependently when instilled intravesically in mice at concentrations of 10-20 mM. Potency was acrolein > 3-oxoPrMCA S-oxide > 3-oxoPrMCA > 3-oxoPrGSH. These data support the possibility that a mercapturic acid may be involved in the bladder toxicity of CP.
• Formation of a Vitamin C Conjugate of Acrolein and Its Paraoxonase-Mediated Conversion into 5,6,7,8-Tetrahydroxy-4-oxooctanal
  作者：Nicholas G. Kesinger、Brandi L. Langsdorf、Alexandre F. Yokochi、Cristobal L. Miranda、Jan F. Stevens

  DOI：10.1021/tx900452j

  日期：2010.4.19

  intermediate carboxylic acid. Subsequent decarboxylation of the carboxylic acid yielded 5,6,7,8-tetrahydroxy-4-oxooctanal (THO). When THP-1 cells were pretreated with ascorbic acid (1 mM, 18 h) and then exposed to acrolein diacetate, THO was detected as its pentafluorobenzyl oxime derivative in the cell lysates and medium. Treatment of THP-1 cells with both ascorbic acid and acrolein diacetate was required

  据报道，维生素 C（抗坏血酸）参与体外迈克尔加成反应，与 α,β-不饱和醛（如丙烯醛）形成维生素 C 缀合物。该研究显示了丙烯醛维生素 C 结合物 (AscACR) 在暴露于丙烯醛二乙酸酯的培养的人类单核细胞 THP-1 细胞中形成和代谢的证据。通过使用18 O 和13C 标记与液相色谱-串联质谱法相结合，显示 AscACR 将抗坏血酸内酯水解转化为中间体羧酸。随后羧酸的脱羧产生 5,6,7,8-四羟基-4-氧代辛醛 (THO)。当 THP-1 细胞用抗坏血酸 (1 mM, 18 h) 预处理，然后暴露于二乙酸丙烯醛时，在细胞裂解物和培养基中检测到 THO 作为其五氟苄基肟衍生物。THO形成需要用抗坏血酸和丙烯醛二乙酸酯处理THP-1细胞。内酯酶、人重组对氧磷酶 1 和 2 促进了 AscACR 形成 THO。THP-1 细胞表现出 PON 活性，这解释了 AscACR 在这些细胞中催化转化为